It is estimated that upwards of 10 million Americans have some form of autoimmune disorder. It is clear that for most of these disorders both genetic and environmental factors contribute to the development and progression of disease. In specific disorders such as systemic lupus erythematosis, women of childbearing age are affected at a rate 9-10 times that of men, and data both from human and animal studies suggest that estrogens can have an adverse impact on the course of the autoimmune process. Recently considerable interest has focused on possible environmental factors that may contribute to the development of autoimmune disorders in general, and lupus in particular. Several chemicals have been shown to have estrogen-like effects, and one mechanism by which environmental toxicants might influence the appearance of severity of autoimmune diseases is by mimicking the effects of estrogen. Preliminary studies in our laboratory have found that three chlorinated pesticides (o,p'-DDT, chlordecone, and methoxychlor) previously shown to have estrogenic effects in vivo significantly accelerate the development of autoimmune disease in a lupus model, (NZB x NZW)F1 (or BW1) mice. A proposed series of experiments 3will extend these observations by establishing dose-response relationships for this effect for each of the three toxicants and determining on-effect levels. To facilitate extrapolation to other species including humans, body burdens in key tissues corresponding to these dosages will be determined. A related objective will be to determine whether autoimmune effects can be elicited by these agents following fetal and neonatal exposure or in a mouse strain that does not normally develop spontaneous lupus. The hypothesis that effects are due to estrogenic activity will be tested in mice administered an estrogen antagonist, and a potential mechanism will be examined. Using o,p'-DDT, methoxychlor, and chlordecone as prototype environment estrogenic autoimmune disease, as well as provide important information regarding mechanisms through which immune function is altered by these agents.